Clinical Impact of the Increase in Immunosuppressive Cell-Related Gene Expression in Urine Sediment during Intravesical Bacillus Calmette-Guérin

• Main Authors: Makito Miyake, Shunta Hori, Sayuri Ohnishi, Takuya Owari, Kota Iida, Kenta Ohnishi, Yosuke Morizawa, Daisuke Gotoh, Yoshitaka Itami, Yasushi Nakai, Takeshi Inoue, Satoshi Anai, Kazumasa Torimoto, Katsuya Aoki, Tomomi Fujii, Nobumichi Tanaka, Kiyohide Fujimoto
• Format: Article
• Language: English
• Published: MDPI AG 2019-06-01
• Series: Diseases
• Subjects: Bacillus Calmette-Guérin; non-muscle invasive bladder cancer; tumor-associated macrophage; regulatory T cell; myeloid-derived suppressor cell; intravesical recurrence
• Online Access: https://www.mdpi.com/2079-9721/7/2/44

Background: The aim of this study is to evaluate the clinical impact of intravesical Bacillus Calmette-Gu&#233;rin (BCG)-induced changes in blood/urinary immune markers. Methods: Time-course changes in blood/urinary clinical parameters and mRNA expression of 13 genes in urine sediment taken eight times during the treatment course of intravesical BCG (before, every 2 weeks for 8 weeks, and after) in 24 patients with non-muscle invasive bladder cancer. The genes examined include cellular markers of four immune checkpoint proteins (PD-L1, PD-L2, PD-1, and CTLA-4), immunosuppressive cells (regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells), pan-T lymphocytes, B lymphocytes, and neutrophils. Results: Significant transient increase in gene expression was observed for PD-L1, PD-1, FOXP3, and CD204 at 6&#8722;8 doses of BCG. The patients were stratified into two groups depending on the number of genes with increased mRNA expression. Fourteen (58%) had 0&#8722;1 genes upregulated, while 10 (42%) had 2&#8722;4 genes with increased expression. No patient in the 0&#8722;1 group experienced recurrence, while 70% of patients in the 2&#8722;4 group experienced recurrence (<i>p</i> value = 0.037, hazard ratio = 5.93). Conclusions: Our findings suggested that increases in more than one of PD-L1, PD-1, FOXP3, and CD204, expression in the urine sediments was associated with resistance to BCG treatment.